Dataset Information

CAND1 regulates lunapark for the proper tubular network of the endoplasmic reticulum.

ABSTRACT: Endoplasmic reticulum (ER) tubules connect each other by three-way junctions, resulting in a tubular ER network. Oligomerization of three-way junction protein lunapark (Lnp) is important for its localization and the three-way junction stability. On the other hand, Lnp has an N-terminal ubiquitin ligase activity domain, which is also important for the three-way junction localization. To understand the mode of action of Lnp, we isolated Cullin-associated and neddylation-dissociated 1 (CAND1), a regulator of Skp1-Cul1-F-box (SCF) ubiquitin ligase, as a Lnp-binding protein by affinity chromatography. CAND1 and Lnp form a higher-molecular-weight complex in vitro, while they do not co-localize at the three-way junctions. CAND1 reduces the auto-ubiquitination activity of Lnp. CAND1 knockdown enhances proteasomal degradation of Lnp and reduces the tubular ER network in mammalian cells. These results suggest that CAND1 has the potency to promote the formation of the higher-molecular-weight complex with Lnp and reduce the auto-ubiquitination activity of Lnp, thereby regulating the three-way junction stability of the tubular ER network.

SUBMITTER: Kajiho H

PROVIDER: S-EPMC6739345 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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CAND1 regulates lunapark for the proper tubular network of the endoplasmic reticulum.

Kajiho Hiroaki H Yamamoto Yasunori Y Sakisaka Toshiaki T

Scientific reports 20190911 1

Endoplasmic reticulum (ER) tubules connect each other by three-way junctions, resulting in a tubular ER network. Oligomerization of three-way junction protein lunapark (Lnp) is important for its localization and the three-way junction stability. On the other hand, Lnp has an N-terminal ubiquitin ligase activity domain, which is also important for the three-way junction localization. To understand the mode of action of Lnp, we isolated Cullin-associated and neddylation-dissociated 1 (CAND1), a re ...[more]

PMID: 31511573

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Project description:ObjectiveThis study aimed to explore the molecular mechanism of cytoplasmic vacuolation caused by BK polyomavirus (BKPyV) and thus search for potential target for drug repurposing.MethodsMorphological features of BK polyomavirus-associated nephropathy (BKPyVAN) were studied under light and electron microscopes. Microarray datasets GSE75693, GSE47199, and GSE72925 were integrated by ComBat, and differentially expressed genes (DEGs) were analyzed using limma. Furthermore, the endoplasmic reticulum (ER)-related genes obtained from GenCLiP 2.0 were intersected with DEGs. GO and KEGG enrichment pathways were performed with intersection genes by R package clusterProfiler. The single-cell RNA sequencing (scRNA-seq) from a BKPyVAN recipient was analyzed with a dataset (GSE140989) downloaded from Gene Expression Omnibus (GEO) as control for gene set variation analysis (GSVA). Immunohistochemistry and electron microscopy of kidney sections from drug-induced ERS mouse models were performed to explore the association of ERS and renal tubular vacuolation. Protein-protein interaction (PPI) network of the intersection genes was constructed to identify hub target. AutoDock was used to screen Food and Drug Administration (FDA)-approved drugs that potentially targeted hub gene.ResultsLight and electron microscopes exhibited obvious intranuclear inclusions, vacuoles, and virus particles in BKPyV-infected renal tubular cells. Transcriptome analysis revealed 629 DEGs between samples of BKPyVAN and stable transplanted kidneys, of which 16 were ER-associated genes. GO analysis with the intersection genes illustrated that ERS-related pathways were significantly involved, and KEGG analysis showed a prominent enrichment of MAPK, Toll-like receptor, and chemokine signaling pathways. GSVA analysis of the proximal tubule revealed similar pathways enrichment. An electron microscope image of the kidney from ERS mouse models showed an obvious renal tubular vacuolation with prominent activation of ERS markers verified by immunohistochemistry. Furthermore, DDIT3 was identified as the hub gene based on PPI analysis, and ZINCOOOOO1531009 (Risedronate) was indicated to be a potential drug for DDIT3.ConclusionERS was involved in renal tubular cytoplasmic vacuolation in BKPyVAN recipients. Risedronate was screened as a potential drug for BKPyVAN by targeting DDIT3.

Dataset Information

CAND1 regulates lunapark for the proper tubular network of the endoplasmic reticulum.

Publications

CAND1 regulates lunapark for the proper tubular network of the endoplasmic reticulum.

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